CHARACTERIZATION OF A NOVEL LOSS OF FUNCTION MUTATION OF PAX8 ASSOCIATED WITH CONGENITAL HYPOTHYROIDISM.

Tina Di Palma (1) , Emilia Zampella (2) , Maria Grazia Filippone (1, 3) , Paolo Emidio Macchia (2) , Carrie Ris-Stalpers (4) , Monique de Vroede (5) , Mariastella Zannini (1)

1 Institute of Experimental Endocrinology and Oncology "G. Salvatore"
2 Dpt. of Molecular and Clinical Endocrinology and Oncology
3 Dpt. of Cellular and Molecular Biology and Pathology
4 Laboratory of Pediatric Endocrinology
5 Division of Pediatric Endocrinology

Background: Congenital hypothyroidism (CH) is a common endocrine disease that occurs in about 1:3000 newborns. In 80-85% of the cases, CH is presumably secondary to thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to an ectopic (30-45%), absent (agenesis, 35-40%) or hypoplastic (5%) thyroid gland. The pathogenesis of TD is still largely unknown. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, mutations in the PAX8 transcription factor have been identified in patients with TD. Objective: Our aim was to identify and functionally characterize novel PAX8 mutations with autosomal dominant transmission responsible for TD. Design: The PAX8 gene was sequenced in a mother and child both suffering for CH due to thyroid hypoplasia. Subsequently, expression vectors encoding the mutated PAX8 were generated and the effects of the mutation on both the DNA binding capability and the transcriptional activity were evaluated. Results: PAX8 gene sequencing revealed an heterozygous mutation, that consists of the substitution of a histidine residue with a glutamine at position 55 of the PAX8 protein (H55Q). When tested in cotransfection experiments with a thyroglobulin promoter reporter construct, the mutant protein turned out to be still able to bind DNA in EMSA assays but transcriptionally inactive. Conclusions: Our findings confirm the important role of PAX8 in normal thyroid development and support the evidence that in humans haploinsufficiency of PAX8 is associated to TD.

Mots clés: Medicine

Tina Di Palma, Emilia Zampella, Maria Grazia Filippone, Paolo Emidio Macchia, Carrie Ris-Stalpers, et al.. CHARACTERIZATION OF A NOVEL LOSS OF FUNCTION MUTATION OF PAX8 ASSOCIATED WITH CONGENITAL HYPOTHYROIDISM.. Clinical Endocrinology, 2010, 73 (6), pp.808. ⟨10.1111/j.1365-2265.2010.03851.x⟩. ⟨hal-00593442⟩